5-Azacytidine (also called as azacytidine or by the product name of Vidaza®) and 2′-deoxy-5-azacytidine (also called as decitabine or by the product name of Dacogen®) have the following chemical structures (i) and (ii), respectively.

It has been known that azacytidine and its 2′-deoxy form (also collectively referred to as “azacytidines or 5-azacytidines” in this specification hereafter) inhibit protein synthesis and some enzymes by incorporating into RNA or DNA during nucleic acid bio-synthesis in frequently dividing cells, and show cytotoxicity (patent documents 1 and 2, non patent document 1).
In the field of anti-oncogene promoter, when incorporating into DNA in cells, the azacytidines combine irreversibly with transferase of DNA methyl group relating to 5-methylation of the cytosine ring in highly risky myelodysplastic syndrome in which the formation of a large amount of the 5-methylated cytosine moiety has been confirmed, and cause enzyme inhibition. As a result, they promote the reactivation of anti-oncogenes and accordingly have been clinically used as therapeutic agents showing remarkable effects on highly risky myelodysplastic syndrome (non patent documents 2, 3, and 4).
However, each of these azacytidines can be easily inactivated by cytidine deaminase, a metabolic hydrolyzing enzyme in blood and liver (non patent document 5). As the current clinical situation, they can hardly be used effectively as therapeutic agents for patients with highly risky myelodysplastic syndrome.
As a countermeasure, a 5′-O-elaidic ester of 5-azacytidine, a compound having resistance to cytidine deaminase (development No. CP-4200), was synthesized (patent document 3) and expected to be used as a therapeutic agent for acute leukemia and myelodysplastic syndrome. However, enough progress has not been made with its clinical investigations (non patent documents 6, 7, and 8).
Besides, the same problem has also been pointed out in case of arabinocytidine (also called as Ara-C or cytarabine), an anticancer agent. 5′-O-elaidic ester of Ara-C (also called as elacytarabine, development No.: CP-4055) (non patent document 9) and 5′-chained dialkyl phosphate derivatives of Ara-C (non patent document 10) were synthesized. Furthermore, a 5′-mono higher alkyl phosphate derivative of Ara-C (cytarabine ocphosphate, product name: Starasid® Capsule) (non patent document 11) has already been clinically used as a therapeutic agent for non-lymphocytic acute leukemia in adults and myelodysplastic syndrome.
On the other hand, 5-azacytidyl acids which are 5′-mono phosphoric acids of 5-azacytidines have resistance to cytidine deaminase, a metabolic hydrolyzing enzyme (non patent document 5). However, they are highly polar substances and therefore can hardly pass through cell membrane (non patent document 12), which is considered as a problem.
In addition, a cyclic phosphate derivative of 5-azacytidine has been reported (patent document 4). However, neither its stability against cytidine deaminase nor detailed evaluations on its biological activities has been disclosed.
A 5′-diphosphate of 5-azacytidine has also been reported recently (patent document 5). However, none of its specific chemical structure, stability against cytidine deaminase, or evaluations on its biological activities has been reported.